As highly active antiretroviral therapy (HAART) becomes increasingly available for the treatment of HIVdisease, drug resistant strains of HIV-1 are emerging that necessitate the use of newer, more expensive drugs, and often result in treatment failure. Sexually transmitted infections (STIs) have been associated with elevated HIV-1 levels in semen, presumably due to promotion of HIV-1 replication in the genital tract by inflammatory cytokines which are upregulated by STIs, or by direct effects on HIV-1 gene expression by the pathogens themselves. A highly prevalent STI, genital Herpes Simplex Virus 2 (HSV-2) infection, has been associated with increased levels of HIV-1 in genital secretions and an increased rate of HIV-1 sexual transmission. Clinical trials are currently underway to determine whether suppression of HSV-2 infection with acyclovir impacts HIV-1 acquisition and transmission rates. To date, studies on HSV-2/HIV interactions have focused on ART-naive populations. The primary objective of this study is to determine whether Herpes Simplex Virus 2 (HSV-2) co-infection in HIV-1 infected men on HAART promotes HIV replication in the genital tract and the evolution of sexually-transmissible drug-resistant HIV-1. Clinically stable HIV-1 infected men on HAART will be tested for HSV-2 antibodies and enrolled into a cross-sectional study to compare levels of HIV-1 RNA and DNA in semen and blood of HSV-2 co-infected vs. HSV-2 uninfected men (n=125 men/group). A longitudinal study will be conducted in the HSV-2/HIV-1 co-infected group to determine whether anogenital HSV-2 reactivation (clinical symptoms and/or genital HSV shedding) is associated with increased genital shedding of HIV-1. The frequency of RTI and PI drug resistance mutations in HIV-1 RNA from genital and paired blood samples will be determined by TRUGENE. We will also investigate whether seminal HSV-2 DNA and HIV-1 RNA levels are correlated with concentrations of seminal inflammatory and immunological factors (cytokines, antibodies, leukocytes and other mediators of innate immunity). This study will provide valuable information concerning potential interactions between genital HSV-2 and HIV-1 infections in HAART patients, and could have important implications for public health policy regarding provision of antiretroviral therapy to HIV-infected persons in populations with a high prevalence of concomitant STIs.